Method for production of methionine from homoserine

ABSTRACT

The invention relates to a method for production of D- and/or L-methionine via D- and/or L-homoserine with subsequent chemical transformation to give methionine.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority to German application no. 102006 004 063.5, filed on Jan. 28, 2006. The contents of this priorapplication is hereby incorporated by reference in its entirety.

The present invention relates to the production of methionine bycombination of biotechnological and chemical steps.

In particular, the present invention relates to the production ofL-homoserine by fermentation and subsequent chemical conversion toL-methionine in one or more steps.

The amino acid methionine is currently produced industrially in largeamounts worldwide and is of considerable commercial importance.

Methionine is employed in many fields such as, for example,pharmaceutical, health and fitness products. In particular, however,methionine is used as feed additive in many feeds for various farmanimals, both the racemic form and also the enantiomerically pure formof methionine being able to be used.

On an industrial scale, methionine is produced chemically via theBucherer-Bergs reaction, which is a variant of Strecker synthesis. Inthis method the starting substances methylmercaptopropionaldehyde(produced from acrolein and methylmercaptan), prussic acid, ammonia andcarbon dioxide are reacted to form5-(2-methylmercaptoethyl)hydantoin(methioninehydantoin), this issubsequently hydrolysed under alkaline conditions to give alkali metalmethioninate and then the methionine is liberated by neutralization withacid, for example sulphuric acid or carbonic acid. Various other methodscan also be used for producing methionine, such as, for example theamidocarbonylation reaction, the hydrolysis of proteins or fermentation.

Since methionine is produced industrially on a large scale, it isdesirable to have an economic but also environmentally friendly processavailable.

Both Strecker synthesis and the Bucherer-Bergs reaction have thedisadvantage that the poisonous precursors prussic acid and acrolein areused as C₁- and C₃-building blocks, respectively. Prussic acid isproduced from methane and ammonia at high temperatures. Acrolein isproduced by partial oxidation of propene which in turn is produced frompetroleum. The methionine process is described in more detail, forexample, in EP 1256571. The process for producing acrolein is describedin more detail, for example, in EP 417723. Both processes are associatedwith high equipment usage and high energy requirement.

Owing to the price increase of petroleum in recent years, acrolein isalso becoming increasingly more expensive and thus as a building blockhas become less and less attractive economically. Furthermore, not onlyprussic acid but also acrolein, because of their toxicity and physicalproperties with respect to safety and environmental protection, giverise to corresponding expenditure in the handling of large amounts.

Methionine is produced in chemical synthesis as a racemic mixture of Dand L enantiomers. This racemate can be used directly as feed additive,since under in vivo conditions, there is a conversion mechanism whichconverts the unnatural D enantiomer into the natural L enantiomer.However, this conversion is associated with a loss of methionine andthus also a loss of bioefficiency compared with the same amount of pureL enantiomer. Therefore, more racemic D,L-methionine is requiredcompared with L-methionine, to achieve the same effect.

It was therefore desirable to provide a process for production ofmethionine which is as far as possible of greater economic interest andmore environmentally friendly and safer. In particular, it was desirableto provide a process for production of enantiomerically enrichedL-methionine, very particularly preferably of as far as possibleenantiomerically pure L-methionine, which should be able to be carriedout on an industrial scale.

Previous processes which are based on the production of L-methionineusing microorganisms as described, for example in WO04/024933, have thedisadvantage that comparatively small yields are achieved. This has itsorigin, in particular, in the problems with the strictly organizedregulatory network of microbial L-methionine biosynthesis, with theexcretion of methionine from the cell into the fermentation broth, andalso with the energy-intensive eight-electron step in the reduction ofsulphate to hydrogen sulphide. Secondly, the limited solubility ofmethionine in water or in aqueous fermentation broths has the effectthat methionine precipitates out at high biosynthesis performance in thefermentation and thus makes purification difficult. The complexpurification leads as a result to the fact that considerable wastestreams are produced, the removal of which is associated with highcosts.

Although in WO05/059155 a method is described for the improved isolationof L-methionine from fermentation broths, the improvement is achieved,however, by a comparatively complicated sequence of steps whichcomprises, heating and dissolving the L-methionine in the fermentationbroth, filtering off the biomass at a defined temperature andpost-treating the methionine-containing biomass which was filtered off,concentrating the mother liquor by evaporation, cooling, crystallizing,filtering off, washing and drying the L-methionine from the motherliquor and recycling mother liquors, and by the fact that two differentproduct streams are produced, namely a low concentration and ahigh-concentration L-methionine product. The forced production of twodifferent methionine quality grades means, however, again increasedexpenditure and is moreover undesirable from the marketing point ofview.

The said problems ultimately lead to a lower overall yield for a purelyfermentative L-methionine method compared with the fermentativeproduction methods of, for example, L-lysine, which have already beenused for many years in industry and/or to a corresponding additionalexpenditure in the production of L-methionine by fermentation.

Against the background of the disadvantages of the prior art, it was, inparticular, the object to provide a method for methionine whichovercomes the above disadvantages described in more detail of the methodof the prior art. This method should, as far as possible proceeding fromanother available precursor and producible by fermentation, lead in thesimplest possible manner and without the use of the abovementionedhazardous chemicals to L-, D- or D,L-methionine, but preferably toL-methionine and in so doing overcome in particular the disadvantages ofthe conventional chemical methods and also of the directbiotechnological production methods for methionine.

It was a further object to provide a production method which can becarried out at least in part starting from natural or renewable rawmaterials.

A third object was to provide a method which can be carried outtechnically without problem, which makes L-methionine accessible insuitable amounts and purities.

These objects and also further objects which are not mentionedexplicitly, but which can be derived or concluded from the contextdiscussed herein without problem, are achieved in that another aminoacid which is available and producible better by fermentation is used asstarting material, which is then converted via a suitable chemicaltransformation without using the abovementioned hazardous chemicals toL-, D- or D,L-methionine, but in particular to L-methionine. By thismeans, not only the disadvantages of the conventional chemicalproduction processes for methionine are overcome, but also those of theconventional production processes for L-methionine by directfermentation. The amino acid homoserine has proved suitable according tothe invention, which, in contrast to methionine, has a high watersolubility and which is also accessible via fermentative methods.

The pathway described by Livak, Britton, VanderWeele and Murray(“Synthesis of dl-methionine”, Journal of the American Chemical Society,(1945), 67, 2218-20) in which D,L-homoserine occurs as synthesisintermediate, proceeds first from D,L-2-amino-4-butyrolactone whichleads via D,L-homoserine, N-carbamoylhomoserine,4-(2-bromomethyl)hydantoin and 4-(2-methylthioethyl)-hydantoin, finallyto D,L-methionine:

The deuterated homoserine derivatives HO—CHD-CH₂—CH(HNCOOtBu)COOtBu orH₃CC₆H₄SO₂O—CHD-CH₂—CH—(HNCOOtBu)COOtBu (tBu=tert-butyl) were usedaccording to Son and Woodard (“Stereochemical mechanism of iodoaceticacid mediated decomposition of L-methionine to L-homoserine lactone”,Journal of the American Chemical Society (1989), 111(4), 1363-7) asprecursors of L-homoserine correspondingly deuterated in the 4 position.The corresponding non-deuterated compounds HO—CH₂—CH₂—CH(HNCOOtBu)COOtBuor H₃CC₆H₄SO₂O—CH₂—CH₂—CH(HNCOOtBu)COOtBu have not been described on thepathway to homoserine.

The subsequently schematized compounds3,6-di(2-hydroxy-ethyl)-2,5-diketopiperazine,3,6-di(2-chloroethyl)-2,5-diketopiperazine or3,6-di(2-methylthioethyl)-2,5-diketopiperazine are chemicalintermediates through which the pathway to D,L-methionine passesaccording to U.S. Pat. No. 2,397,628, however, starting not fromhomoserine, but starting from 2-acetyl-4-butyrolactone:

In addition there are further production methods for D,L-methioninewhich likewise do not start from homoserine, but start, for example,from 2-acetyl-4-butyrolactone via 2-amino-4-butyrolactone orappropriately protected 2-amino-4-butyrolactone, according to Snyder,Andreen, John, Cannon and Peters (“Convenient synthesis ofdl-methionine”, Journal of the American Chemical Society (1942), 64,2082-4).

The synthesis according to Plieninger starts from2-amino-4-butyrolactone (“Die Aufspaltung des γ-Butyrolactons undα-Amino-γ-butyrolactons mit Natriummethyl-mercaptid bzw. -selenid. EineSynthese des Methionins” [The Cleavage of γ-Butyrolactone andα-Amino-γ-butyrolactone using Sodium Methyl Mercaptide or Selenide. ASynthesis of Methionine], Chemische Berichte (1950), 83, 265-8).

The subsequently schematized compounds, 3,6-di-(2-vinyl)-2,5-diketopiperazine and 3,6-di(2-bromoethyl)-2, 5-diketopiperazine arelikewise chemical precursors

through which, according to Snyder and Chiddix (“Non-Markovnikovaddition in reactions of 3,6-divinyl-2, 5-diketopiperazine”, Journal ofthe American Chemical Society (1944), 66, 1002-4) the pathway toD,L-methionine passes. However, here also homoserine is not used.

In particular, the abovementioned objects are achieved by a methodaccording to Claim 1. Expedient forms and modifications of the inventivemethod are brought under protection in the subclaims referred back toClaim 1.

By the means that a method is used for production of L-methionine,D-methionine or any desired mixtures of L- and D-methionine which startsfrom homoserine and in which L-homoserine, D-homoserine or correspondingmixtures of L- and D-homoserine of the formula I below

are converted to methionine by chemical transformation, without passingthrough any of the intermediates N-carbamoylhomoserine,4-(2-bromoethyl)hydantoin and 4-(2-methylthioethyl)hydantoin (formulaeA-C),

the disadvantages of the said purely chemical or direct biotechnologicalmethods are successfully overcome.

These disadvantages are overcome, in particular, when the L-homoserineused has been produced via fermentation. It is already known thatL-homoserine can be produced by fermentation of microorganisms, inparticular bacteria of the family Enterobacteriaceae or coryneformbacteria, with carbon sources such as, for example, sucrose, glucose,fructose and glycerol or mixtures thereof and customary nitrogen sourcessuch as, for example, ammonia being used.

Examples of the microbial production of L-homoserine in whichEnterobacteriaceae, in particular Escherichia coli, are used, can befound in U.S. Pat. No. 6,303,348, U.S. Pat. No. 6,887,691 or U.S. Pat.No. 6,960,455 or EP 1217076 A1.

Examples of the microbial production of L-homoserine in which coryneformbacteria, in particular Corynebacterium glutamicum, are used, can befound in U.S. Pat. No. 3,189,526 or U.S. Pat. No. 3,598,701.

By using L-homoserine obtained by fermentation, the said relativelyhazardous raw materials acrolein and prussic acid are successfullyavoided.

However, it can also be advantageous to mix L-homoserine obtained byfermentation with racemic D,L-homoserine produced classically by thechemical route and to use a resulting mixture of D- and L-homoserine forthe chemical transformation, from which at the end then correspondingmixtures of D- and L-methionine result. This can be advantageous,especially, when D-/L-homoserine is to be utilized as residue ofchemical production processes of D-/L-homoserine production. PureD-homoserine can also be used. This can be advantageous, in particular,when D-homoserine is to be utilized as residue from the separation ofD-/L-homoserine racemate. The use of pure D-homoserine, however, isgenerally only advantageous when D-methionine is to be producedspecifically.

By use of L-homoserine obtained by fermentation, it is possible, incontrast, to arrive directly at L-methionine and in fact with the useaccording to the invention of chemical method steps which do not impairthe L configuration. In the case of exclusive use of L-homoserine,ultimately a pure L-methionine is produced which can be used directlyfor pharmaceutical and food uses and is distinguished in animalnutrition by higher bioefficiency compared with conventionalD,L-methionine. This aspect of the method of the invention is generallyof greatest benefit.

In a preferred method, use is made of an L-homoserine-containing solidproduct which was produced from an L-homoserine-containing fermentationbroth by removal of water. This has the advantage that byproducts offermentation can first be separated off in the L-methionine stage in thelast purification step, and thus purification expenditure can be saved.If appropriate, byproducts and/or accompanying substances offermentation can also remain in the end product if they do not interferewith the subsequent reaction or are even desired in the end product.This is the case, in particular, if they themselves have nutritiousproperties and L-methionine is used for feed production. Suchnutritionally active compounds can be, for example, further amino acidsor proteins.

Accordingly, the invention also relates to a mixed product ofL-methionine and byproducts and/or accompanying substances of theproduction of L-homoserine by fermentation.

The L-homoserine-containing fermentation broth is expediently producedby culturing an L-homoserine-excreting microorganism in a suitablenutrient medium.

As microorganism, use is preferably made of bacteria, in particularbacteria of the genus Corynebacterium or Escherichia.

It has furthermore proved to be advantageous when the concentration ofthe L-homoserine in the fermentation broth is at least 1 g/l.

Surprisingly, it has been found that the chemical transformation of L-and/or D-homoserine can be carried out directly using methylmercaptan(MeSH) if appropriate in the presence of an acid catalyst. This has thegreat advantage that a single chemical step leads directly to the endproduct L-methionine. Methylmercaptan can be used here in great excessesand unconsumed methylmercaptan can subsequently readily be separated offand recycled, since, in contrast to the amino acid, it is a compoundgaseous at room temperature.

Here, it has proved advantageous to use 1 to 100 mol equivalents,preferably 1 to 50 mol equivalents, of MeSH.

To accelerate the reaction and to increase the yield, it has also provedadvantageous when use is made of an acid catalyst selected from thegroup consisting of Brönstedt acids having a pK_(a) of ≦3.

Such acids are, for example, HCl, HBr, HI, H₂SO₄, alkali metal HSO₄,H₃PO₄, alkali metal H₂PO₄, where alkali metal is lithium, sodium,potassium, rubidium or caesium, polyphosphoric acid,C₁-C₁₂-alkylsulphonic acid, C₆-C₁₀-arylsulphonic acid,trifluoromethanesulphonic acid, trifluoroacetic acid, or a copolymer oftetrafluoroethylene and perfluoro-3,6-dioxo-4-methyl-7-octenesulphonicacid (Nafion). Nafion as solid catalyst has the advantage, inparticular, that it can readily be separated off from the reactionmixture after the reaction and be recycled.

It can likewise be advantageous when use is made of a Lewis acidcatalyst. Here, mention may be made of, in particular, Lewis acidcatalysts having at least one low-molecular-weight Lewis acid selectedfrom the group AlCl₃, ZnCl₂, BF₃·OEt₂, SnCl₂, FeCl₃.

Also, strongly acidic ion-exchange resins which likewise can berecovered particularly readily, have proved advantageous here, inparticular an optionally substituted, for example by divinylbenzene,crosslinked polystyrenesulphonic acid resin.

However, heterogeneous acid catalysts from the group zeolite,montmorrillonite and (WO₃- and Cs₂O)-containing aluminium oxide can alsobe used according to the invention. Among the said aluminium oxides,preference is given to those having 5-15% WO₃ and 5-15% Cs₂O content.

Expediently, the reaction is carried out in solution and/or insuspension in the presence of water and/or an organic solvent. If thereaction is carried out in the presence of water, it can be expedient toproceed directly from an L-homoserine-containing aqueous fermentationsolution, which is optionally freed from solid fractions, since in thismanner advantageously, further work-up steps can be omitted. However, anaqueous crude L-homoserine can also be correspondingly advantageouslyused.

For instance, according to the invention, use can be made of waterand/or at least one low-molecular-weight organic solvent selected fromthe group consisting of C₃ to C₆ ketones, preferably methyl isobutylketone (MIBK) or acetone, straight-chain or branched C₁ to C₄ alcohols,C₄ to C₁₀ carboxylic esters, preferably ethyl or butyl acetate, C₃ to C₆carboxamides, preferably DMF or dimethylacetamide, C₆ to C₁₀ aromatics,preferably toluene, and C₃ to C₇ cyclic carbonates, preferably ethylenecarbonate, propylene carbonate, butylene carbonate. However,methylmercaptan, used in corresponding excesses, can also act as solventor at least as cosolvent.

According to another preferred embodiment of the invention, a method forthe chemical transformation of L- and/or D-homoserine to methionine canalso be carried out in such a manner that, in a first step, byintroduction of a leaving group Y on the C₄ atom of homoserine, acompound of the formula II

is produced, where Y is halogen(=chlorine, bromine or iodine),sulphonyloxy(=p-toluenesulphonyloxy [pTsO], C₆H₅SO₃, H₃CSO₃, H₅C₂SO₃ orCF₃SO₂), sulphate (OSO₃H) or phosphate (OPO₃H), and compound II is thenreacted in a second step with MeSH to give L-methionine, D-methionine ora corresponding mixture of L- and D-methionine.

Introduction of the leaving group Y proceeds advantageously, whenY=halogen, in the first step correspondingly by reaction of thehomoserine with PCl₅, PCl₃, BBr₃, PJ₃, POCl₃, SOCl₂ or SOBr₂.

When Y=sulphonyloxy, introduction of the leaving group Y in the firststep proceeds correspondingly and advantageously by reaction withp-toluenesulphonyl chloride (p-TsCl), C₆H₅SO₂Cl, H₃CSO₂Cl, H₅C₂SO₂Cl orCF₃SO₂Cl.

When, in contrast, Y=sulphate, for introduction of the leaving group Y,in the first step typically use is correspondingly made of SO₃, H₂SO₄ oroleum, and when Y=phosphate, preferably use is made of polyphosphoricacid to introduce Y.

After activation of the homoserine by introducing the correspondingleaving group Y in the 4 position, in a next step, the Me-S group may beparticularly readily introduced by substitution of Y.

This substitution is advantageously carried out by reacting the compoundof the formula II with MeSH in the presence of a basic or acid catalyst.

Suitable basic catalysts are, in particular, NaOH, KOH, pyridine,trimethylamine, triethylamine or an acetate, carbonate orhydrogencarbonate of the alkali metals or alkaline earth metals, alkalimetal being lithium, sodium, potassium, rubidium or caesium and alkalineearth metal being magnesium, calcium or barium.

Suitable acid catalysts are, in particular, HCl, HBr, HI, H₂SO₄, alkalimetal HSO₄, H₃PO₄, alkali metal H₂PO₄, where alkali metal is lithium,sodium, potassium, rubidium or caesium, polyphosphoric acid,C₁-C₁₂-alkyl-sulphonic acid, C₆-C₁₀-arylsulphonic acid,trifluoromethanesulphonic acid, trifluoroacetic acid, or a copolymer oftetrafluoroethylene and perfluoro-3, 6-di-oxo-4-methyl-7-octenesulphonicacid (Nafion) is used.

The reaction is preferably carried out in the presence of an organicsolvent and/or water.

As organic solvent, use is preferably made of a low-molecular-weightorganic solvent selected from the group consisting of C₃ to C₆ ketones,preferably methyl isobutyl ketone (MIBK) or acetone, straight-chain orbranched C₁ to C₄ alcohols, C₄ to C₁₀ carboxylic esters, preferablyethyl or butyl acetate, C₃ to C₆ carboxamides, preferably DMF ordimethylacetamide, C₆ to C₁₀ aromatics, preferably toluene, and C₃ to C₇cyclic carbonates, preferably ethylene carbonate, propylene carbonate orbutylene carbonate.

According to a further preferred embodiment of the invention, a methodfor the chemical transformation of L- and/or D-homoserine to methioninecan also be carried out in such a manner that, in a first step, byacid-catalysed cyclization, the corresponding 2-amino-4-butyrolactone ofthe formula III or salt thereof (formula IV)

is produced, where X is Cl, Br, I, HSO₄, (SO₄)_(1/2), H₂PO₄,(HPO₄)_(1/2), (PO₄)_(1/3) or R′—-SO₃ (where R′=methyl, ethyl, phenyl,tosyl), which is then reacted in a second step with MeSH to giveL-methionine, D-methionine or a corresponding mixture of L- andD-methionine. In particular, the salt is a stable intermediate which canbe temporarily stored or else transported, which is a not inconsiderableadvantage.

Suitable acid catalysts are acids selected from the group consisting ofBrönstedt acids having a pK_(a) of ≦3.

Preferably, as acid catalyst, use is made here of HCl, HBr, HI, H₂SO₄,alkali metal HSO₄, H₃PO₄, alkali metal H₂PO₄, where alkali metal islithium, sodium, potassium, rubidium or caesium, polyphosphoric acid,C₁-C₁₂-alkylsulphonic acid, C₆-C₁₀-arylsulphonic acid,trifluoromethanesulphonic acid, trifluoroacetic acid or a copolymer oftetrafluoroethylene and perfluoro-3,6-dioxo-4-methyl-7-octenesulphonicacid (Nafion).

Likewise, strongly acidic ion-exchange resins are suitable as acidcatalyst and in this case in particular optionally substituted,preferably by divinylbenzene, crosslinked polystyrenesulphonic acidresins.

Use can also be made of heterogeneous acid catalysts from the group(WO₃- and Cs₂O)-containing aluminium oxide, zeolite and montmorrilloniteaccording to the invention. Among the said aluminium oxides, preferenceis given to those having 5-15% WO₃ content and 5-15% Cs₂O content.

Likewise, use can be made of Lewis acid catalysts and, in particular,low-molecular-weight Lewis acids selected from the group AlCl₃, ZnCl₂,BF₃·OEt₂, SnCl₂, FeCl₃, which are available and inexpensive.

According to a further preferred embodiment of the invention, a methodfor the chemical transformation of homoserine to methionine can also bedesigned in such a manner that the following steps are carried out:

-   a) N-acylation of L- and/or D-homoserine using an acylating agent to    give N-acyl-L- and/or D-homo-serine of the formula V,

-   -   where R=hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl,        sec-butyl, tert-butyl, phenyl, mono-, di- or trihaloalkyl, where        halogen=F or Cl, preferably CF₃ or CCl₃, benzyloxycarbonyl or        C₁- to C₄-alkyloxycarbonyl, preferably tert-butyl-oxycarbonyl,        or methyloxycarbonyl,

-   b) reaction of the N-acylhomoserine V obtained in step a) with MeSH    in the presence of a basic or acid catalyst to give N-acylmethionine    of the formula VI

-   c) hydrolysis of the N-acyl-L— and/or D-methionine obtained in    step b) to give the corresponding methionine.

Depending on the exact choice of reaction conditions, in step a) eitherthe corresponding O-acylhomoserine is primarily formed which issubsequently rearranged to form the N-acylhomoserine V, or V is formeddirectly in one stage.

For the acylation in step a), preferably use is made of an acylatingagent of the general formula R—CO—X¹, where X¹ can be R¹COO, OR²(R²=methyl or ethyl), Cl, Br, and R and R¹ can be identical or differentand are hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, tert-butyl, phenyl, mono-, di- or trihaloalkyl, wherehalogen=F or Cl, preferably CF₃ or CCl₃, benzyloxycarbonyl, or C₁- toC₄-alkyloxycarbonyl, preferably tert-butyloxycarbonyl, ormethyloxycarbonyl.

As basic catalyst in step b), use can be made of NaOH, KOH, pyridine,trimethylamine, triethylamine, or an acetate, carbonate orhydrogencarbonate of the alkali metals or alkaline earth metals, wherealkali metal is lithium, sodium, potassium, rubidium or caesium, andalkaline earth metal is magnesium, calcium or barium.

Suitable acid catalysts for step b) are, in particular, HCl, HBr, HI,H₂SO₄, alkali metal HSO₄, H₃PO₄, alkali metal H₂PO₄, where alkali metalis lithium, sodium, potassium, rubidium or caesium, polyphosphoric acid,C₁-C₁₂-alkylsulphonic acid, C₆-C₁₀-arylsulphonic acid,trifluoromethanesulphonic acid, trifluoroacetic acid, or a copolymer oftetrafluoroethylene and perfluoro-3,6-dioxo-4-methyl-7-octenesulphonicacid (Nafion).

According to a further preferred embodiment of the invention, a methodfor the chemical transformation of homoserine to methionine can also bedesigned in such a manner that the following steps are carried out:

-   a) N-acylation of the L- and/or D-homoserine using an acylating    agent to give the N-acyl-L- and/or D-homoserine of the formula V

-   -   where R is hydrogen, methyl, ethyl, n-propyl, isopropyl,        n-butyl, sec-butyl, tert-butyl, phenyl, mono-, di- or        trihaloalkyl, where halogen=F or Cl, preferably CF₃ or CCl₃,        benzyloxycarbonyl or C₁- to C₄-alkyloxycarbonyl, preferably        tert-butyloxycarbonyl, or methyloxycarbonyl,

-   b) conversion of the compound V obtained in step a) by introduction    of a leaving group Y on the C4 atom into a compound of the formula    VI

-   -   where Y is halogen(=chlorine, bromine or iodine),        sulphonyloxy(=pTsO, C₆H₅SO₃, H₃CSO₃ or H₅C₂SO₃), sulphate        (OSO₃H) or phosphate (OPO₃H),

-   c) reaction of the compound VI obtained in step b) with MeSH in the    presence of a basic or acid catalyst to give N-acyl-L-methionine,    N-acyl-D-methionine or a corresponding mixture of N-acyl-L- and/or    D-methionine of the formula VII

-   d) hydrolysis of the N-acyl-L- and/or D-methionine VII obtained in    step c) to give L- and/or D-methionine.

The compound V is formed, depending on exact choice of the reactionconditions, either by rearrangement of the O-acylhomoserine primarilyformed to give N-acylhomoserine, or by a combination of in-situlactonization and acylation with subsequent ring opening.

For the acylation in step a), use is preferably made of an acylatingagent of the general formula R—CO—X¹, where X¹=R¹COO, OR² (R²=methyl orethyl), Cl or Br and R and R¹ can be identical or different and arehydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, phenyl, mono-, di- or trihaloalkyl, where halogen=F or Cl,preferably CF₃ or CCl₃, benzyloxycarbonyl or C₁- to C₄-alkyloxycarbonyl,preferably tert-butyloxycarbonyl, or methyloxycarbonyl.

The introduction of the leaving group Y proceeds advantageously, whenY=halogen, in the first step correspondingly by reaction of thehomoserine with PCl₃, BBr₃, PI₃, SOCl₂ or SOBr₂.

When Y=sulphonyloxy, the introduction of the leaving group Y in thefirst step proceeds correspondingly and advantageously by reaction withp-toluenesulphonyl chloride (p-TsCl), C₆H₅SO₂Cl, H₃CSO₂Cl, H₅C₂SO₂Cl orCF₃SO₂Cl. When, in contrast, Y=sulphate, for the introduction of theleaving group Y, in the first step typically use is correspondingly madeof SO₃, H₂SO₄ or oleum. When Y=phosphate (OPO₃H), for the introductionof the leaving group Y, use is made in the first step typically ofpolyphosphoric acid.

After activation of the N-acylhomoserine by introduction of thecorresponding leaving group Y in the 4 position, it is possible tointroduce the Me-S group particularly readily in a next step viasubstitution of Y.

Suitable basic catalysts in step c) are, in particular, NaOH, KOH,pyridine, trimethylamine, triethylamine, or an acetate, carbonate orhydrogencarbonate of the alkali metals or alkaline earth metals, wherealkali metal is lithium, sodium, potassium, rubidium or caesium andalkaline earth metal is magnesium, calcium or barium.

Suitable acid catalysts in step c) are, in particular, HCl, HBr, HI,H₂SO₄, alkali metal HSO₄, H₃PO₄, alkali metal H₂PO₄, where alkali metalis lithium, sodium, potassium, rubidium or caesium, polyphosphoric acid,C₁-C₁₂-alkylsulphonic acid, C₆-C₁₀-arylsulphonic acid,trifluoromethanesulphonic acid, trifluoroacetic acid, or a copolymer oftetrafluoroethylene and perfluoro-3,6-dioxo-4-methyl-7-octenesulphonicacid (Nafion).

According to a further preferred embodiment of the invention, a methodfor the chemical transformation of L- and/or D-homoserine to methioninecan also be designed in such a manner that the following steps arecarried out:

-   a) N-acylation and cyclization of the L- and/or D-homoserine using    an acylating agent to give the N-acyl-L- and/or D-homoserine lactone    of the formula VIII

-   -   where R is hydrogen, methyl, ethyl, n-propyl, isopropyl,        n-butyl, sec-butyl, tert-butyl, phenyl, mono-, di- or        trihaloalkyl, where halogen=F or Cl, preferably CF₃ or CCl₃,        benzyloxycarbonyl or C₁- to C₄-alkyloxycarbonyl, preferably        tert-butyl-oxycarbonyl, or methyloxycarbonyl,

-   b) reaction of the N-acylhomoserine lactone obtained in step a) with    MeSH in the presence of a basic or acid catalyst to give the    corresponding N-acyl-methionine of the formula VII

-   c) hydrolysis of the N-acyl-L- and/or D-methionine obtained in    step b) to give the corresponding methionine at temperatures of >95°    C.

For the acylation in step a), preferably use is made of an acylatingagent of the general formula R—CO—X¹, where X¹=R¹COO, OR² (R²=methyl orethyl), Cl or Br, and R and R¹ can be identical or different and arehydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, phenyl, mono-, di- or trihaloalkyl, where halogen=F or Cl,preferably CF₃ or CCl₃, benzyloxycarbonyl or C₁- to C₄-alkyloxycarbonyl,preferably tert-butyloxycarbonyl or methyloxycarbonyl. The N-acetylationin step a) proceeds either by rearrangement of O-acylhomoserineprimarily formed to give the N-acylhomoserine with subsequent ringclosure, or by a combination of in-situ lactonization and directN-acylation.

Furthermore, in the acylation in step a), as solvent, preferably use ismade of a carboxylic acid RCOOH or R¹COOH, where R or R¹ have themeaning given above, if appropriate in the presence of a furthercosolvent from the group consisting of C₃ to C₆ ketones, preferably MIBKor acetone, C₄ to C₁₀ carboxylic esters, preferably ethyl or butylacetate, C₃ to C₆ carboxamides, preferably DMF or dimethylacetamide, C₆to C₁₀ aromatics, preferably toluene, and C₃ to C₇ cyclic carbonates,preferably ethylene carbonate, propylene carbonate or butylenecarbonate.

As basic catalysts in step a), use is preferably made of pyridinederivatives, preferably dimethylaminopyridine (DMAP), orcarbonyldiimidazole.

Step a) is carried out preferably at temperatures of 20 to 100° C., inparticular at 50 to 90° C.

As basic catalyst in step b), preferably use is made of a catalyst whichis selected from the group consisting of tetraalkylammonium hydroxideshaving a maximum of 48 carbon atoms, hydroxides, carbonates,hydrogen-carbonates, acetates of alkali metals or alkaline earth metals,where alkali metal is lithium, sodium, potassium, rubidium or caesiumand alkaline earth metal is magnesium, calcium or barium, tertiaryamines having a maximum of 36 carbon atoms and 1 to 4 nitrogen atoms,tetra(C₁-C₄-alkyl)guanidine, bicyclic amines, preferably DBU(1,8-diazobicyclo[5.4.0]undec-7-ene) and TBD(1,5,7-triazabicyclo[4.4.0]dec-5-ene), pyridine and strongly alkalineion-exchange resins.

Other preferably used basic catalysts in step b) are trialkylamines ofthe general formula NR³R⁴R⁵, where R³, R⁴ and R⁵ can be identical ordifferent and are a linear or branched C₁- to C₁₂-alkyl radical,preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or sec-butyl.

Very particularly preferred basic catalysts are N(methyl)₃,N(methyl)₂(ethyl), N(methyl)(ethyl)₂, N(ethyl)₃, N(n-propyl)₃,N(ethyl)(isopropyl)₂ or N(n-butyl)₃, but also diazabicyclooctane(DABCO), DBU, TBD, hexamethylenetetramine, tetramethylethylenediamine ortetramethylguanidine.

Likewise, particularly preferably, as basic catalysts, use is made ofR³R⁴R⁵R⁶N-hydroxide, Li—, Na—, K—, Rb—, Cs-hydroxide, Mg—, Ca—,Ba-hydroxide, where R³, R⁴, R⁵ and R⁶ can be identical or different andare a linear or branched C₁- to C₁₂-alkyl radical, preferably methyl,ethyl, n-propyl, isopropyl, n-butyl or sec-butyl.

As particularly preferred basic catalysts, use is also made ofR⁷R⁸NR⁹-substituted crosslinked polystyrene resins, where R⁷, R⁸ and R⁹can be identical or different and are a linear or optionally branchedC₁- to C₄-alkyl radical, preferably methyl, ethyl, n-propyl, n-butyl.

To achieve a rapid and as complete as possible sequence of the reactionin step b), use is made of 1 to 20 mol equivalents of base, calculatedas hydroxide or N equivalent, preferably 1 to 10 mol equivalents ofbase.

If in step b), however, an acid catalyst is used, then it isadvantageous to make use of an acid catalyst selected from the groupconsisting of Brönstedt acids having a pK_(a) of ≦3, or Lewis acids.

Preferably, as acid catalysts, use is made of HCl, HBr, HI, H₂SO₄,alkali metal HSO₄, H₃PO₄, alkali metal H₂PO₄, where alkali metal islithium, sodium, potassium, rubidium or caesium, polyphosphoric acid,C₁-C₁₂-alkyl-sulphonic acid, C₆-C₁₀-arylsulphonic acid,trifluoromethanesulphonic acid, trifluoroacetic acid or a copolymer oftetrafluoroethylene and perfluoro-3,6-dioxo-4-methyl-7-octenesulphonicacid (Nafion).

However, as acid catalysts, use can also be made of strongly acidicion-exchange resins which can readily be separated off after reaction iscomplete.

In this case use is preferably made of optionally substituted,preferably by divinylbenzene, crosslinked polystyrenesulphonic acidresins.

Use can also be made of heterogeneous acid catalysts from the group(WO₃- and Cs₂O)-containing aluminium oxide, zeolite andmontmorrillonite. Among the said aluminium oxides, those having 5-15%WO₃ and 5-15% Cs₂O content are preferred.

Also, use is advantageously made of Lewis acid catalysts.

As Lewis acid, use is preferably made of a low-molecular-weight Lewisacid selected from the group AlCl₃, ZnCl₂, BF₃·OEt₂, SnCl₂, FeCl₃.

It is also advantageous if the reaction in step b) is carried out insolution and/or in suspension in an organic solvent.

As solvent, use can be made of water and/or at least onelow-molecular-weight organic solvent selected from the group consistingof C₃ to C₆ ketones, preferably MIBK or acetone, straight-chain orbranched C₁ to C₄ alcohols, C₄ to C₁₀ carboxylic esters, preferablyethyl or butyl acetate, C₃ to C₆ carboxamides, preferably DMF ordimethylacetamide, C₆ to C₁₀ aromatics, preferably toluene, and C₃ to C₇cyclic carbonates, preferably ethylene carbonate, propylene carbonate orbutylene carbonate.

The hydrolysis in step c) can be carried out in aqueous solution and/orsuspension.

In addition, however, it can also be advantageous if use is madeadditionally of at least one low-molecular-weight organic solvent whichis selected from the group consisting of C₃ to C₆ ketones, preferablyMIBK or acetone, straight-chain or branched C₁ to C₄ alcohols, C₄ to C₁₀carboxylic esters, preferably ethyl or butyl acetate, C₃ to C₆carboxamides, preferably DMF or dimethylacetamide, C₆ to C₁₀ aromatics,preferably toluene, and C₃ to C₇ cyclic carbonates, preferably ethylenecarbonate, propylene carbonate or butylene carbonate.

The reaction in step c) is generally carried out at a temperature of 90to 180° C., preferably at 100 to 160° C., in particular at 120 to 150°C., very particularly preferably at 130 to 140° C.

To accelerate the hydrolysis reaction in step c), the procedure can becarried out in addition in the presence of an acid, basic or Lewis acidcatalyst, or a combination of acid and Lewis acid catalyst.

A methionine process which comprises an inventive combination ofbiotechnological and chemical steps has in total more advantagescompared with a conventional process, in particular with respect to thementioned requirement for a more economic, more reliable process whichin addition should supply L-methionine.

Firstly, the use of sugar instead of propene (or acrolein) makes itpossible to design the methionine production more economically, firstlyfrom the point of view of current raw material costs, and secondly owingto the independence on continuously increasing costs for crude oilachieved.

Secondly, the sugar being used is a renewable raw material, so that herea valuable contribution to conservation of resources is achieved. Inaddition, sugar is far less dangerous than the industrial intermediatesacrolein and prussic acid, so that substitution of sugar for these rawmaterials as starting material significantly reduces the risk potentialof a production process and thus increases safety.

Thirdly, the combination of a fermentation step which makes possible theenantiospecific production of L-homoserine, makes possible, usingsuitable comparatively mild chemical method steps, the conversion ofL-homoserine to L-methionine without racemization and in this mannerleads to enantiomerically pure L-methionine. As mentioned, L-methioninehas a higher bioavailability compared with currently producedD,L-methionine.

Fourthly, the production of enantiomerically pure L-methionine using acombined production process of the type described above permits theproblems mentioned at the outset to be overcome elegantly, whichproblems are associated with production of L-methionine in a purelybiotechnological way.

The inventive examples hereinafter serve for more detailed explanationof the invention without restricting the invention in any way, however.

Direct reaction of L-homoserine to give L-methionine

EXAMPLE 1

Reaction with a heterogeneous catalyst (7-10% WO₃/7-10% Cs₂O on Al₂O₃support—manufacturer—Degussa).

L-Homoserine (biotechnologically produced) and the finely groundheterogeneous catalyst were charged into the autoclave and MeSH wasadded as liquid. The autoclave was subsequently heated to 140° C. over2.5 h. After expansion and removal of MeSH, the system was flushed witha 20% aqueous NaOH solution. The subsequent filtration and HPLC analysisgave a yield of 3% of theory of L-methionine.

In comparison: A similar attempt using a pure Al₂O₃ support gave onlytraces of methionine.

EXAMPLE 2 Reaction with isopropylthiol (iPrSH) and acid/Lewis acid (Doesnot come Under the Claims)

iPrSH (20 ml) was treated slowly with gaseous HBr. SubsequentlyL-homoserine (10 mmol) was added and the mixture was stirred for 10minutes. Thereafter, AlCl₃ (40 mmol) was added and the reaction mixturewas stirred for 4 h at room temperature. The reaction mixture wasquenched using H₂O/HCl and then made basic with NaOH. After filteringoff Al(OH)₃ by suction the filtrate solution was concentrated to drynessand analysed by HPLC. Yield of (1)=8.2%.Activation of L-homoserine at the C-4 atom and reaction to giveL-methionine

EXAMPLE 3 Activation by sulphate with subsequent nucleophilicsubstitution by NaSMe

L-Homoserine (19.4 mmol) was admixed with concentrated H₂SO₄ (10 ml)with cooling. The resultant reaction mixture was stirred in the courseof 30 minutes until the homoserine was dissolved. Subsequently thesolution was allowed to stand for 3 hours at room temperature.Thereafter the reaction solution was added to 800 ml of diethyl ethercooled to −78° C., stirred well and the supernatant solution wasdecanted off. The solid was washed 3 times each time with 200 ml ofdiethyl ether at −78° C. After filtering off the whitish-yellow solid bysuction, it was dried for 2 hours in an oil-pump vacuum. Yield ofsulphate ester (2): 88.0%.

The sulphate ester (19 mmol) was dissolved in DMSO (20 ml) and admixedwith NaSMe (50 mmol). This reaction solution was stirred at 80° C. andanalysed after 90 minutes by HPLC-L-methionine yield: 19.6%. Repetitionof the experiment in N-methylpyrrolidone (NMP) as solvent gave 33.6%L-methionine after 10 minutes.

Cyclization of L-homoserine and further reaction to give L-methionine

EXAMPLE 4 Production of 2-amino-4-butyrolactone hydrochloride salt

Activation by lactone formation with subsequent nucleophilicsubstitution by MeSH

L-Homoserine (0.84 mol) was admixed with 600 ml of concentrated HCl (6.1mol). The solution was stirred for about 15 minutes until everything haddissolved, and subsequently the water was removed under vacuum over thecourse of 1.5 hours. The residue was dried. Yield: 99% of2-amino-4-butyrolactone hydrochloride salt.

EXAMPLE 5 Reaction of 2-amino-4-butyrolactone hydrochloride salt to giveL-methionine

The 2-amino-4-butyrolactone hydrochloride salt (22 mmol) was chargedinto the autoclave in HCl-saturated ethanesulphonic acid (0.2 mol) andMeSH (0.83 mol) was added to this mixture in liquid form. Subsequentlythe autoclave was sealed and heated for 5 hours at 70° C. Afterexpansion and cooling, the reaction solution was analysed by HPLC. TheL-methionine yield was 21%.

EXAMPLE 6 Reaction of 2-amino-4-butyrolactone hydrobromide Salt to giveL-methionine

In a high-pressure autoclave, aluminium bromide (75 mmol) was carefullyadded to MeSH (50 ml). Subsequently, the bromide salt of theaminolactone (obtained from Aldrich) (25 mmol) was added. The autoclavewas shaken for 1 hour at room temperature and thereafter for 2 hours at40° C. The autoclave was cooled and expanded. After removal of the MeSH,the residue was quenched with water and the pH made basic using NaOH.The resultant precipitate was removed by filtration. The methionineyield was 33%.

EXAMPLE 7 Reaction of 2-amino-4-butyrolactone hydrochloride salt to sive2-amino-4-methylthiobutyric acid

The chloride salt of the aminolactone (10 mmol) and also AlCl₃ (30 mmol)were charged into an autoclave and slowly admixed with MeSH (30 ml) andstirred.

Subsequently the mixture was stirred for 71 hours at room temperature.After quenching the reaction mixture with water, the yield of2-amino-4-methylthiobutyric acid was determined by HPLC as 27%.

EXAMPLE 8 Reaction of 2-amino-4-butyrolactone hydrochloride salt to give2-amino-4-isopropyl-thiobutyric acid (does not come under the patentclaims)

i-Propylthiol (iPrSH, 20 ml) was admixed with AlCl₃ (30 mmol) andstirred. Subsequently the chloride salt of the aminolactone (10 mmol)was added and the mixture was stirred for 24 hours at room temperature.After quenching the reaction mixture with water, the yield of2-amino-4-isopropylthiobutyric acid was determined as 77% by HPLC.

EXAMPLE 9 Reaction of 2-amino-4-butyrolactone hydrochloride salt to giveL-methionine

The 2-amino-4-butyrolactone hydrochloride salt (70 mmol) and TBD(1,5,7-triazabicyclo[4.4.0]dec-5-ene) (140 mmol) were charged into theautoclave and liquid MeSH was added. The sealed autoclave was heated to70° C. over 2.5 hours. Subsequently the autoclave was gently cooled andexpanded. The MeSH was removed and the residue analysed by HPLC. TheL-methionine yield was 21%.

EXAMPLE 10 Cyclization of L-homoserine and N-acylation to giveN-acyl-2-amino-4-butyrolactone and further reaction to giveN-acyl-L-methionine (precursor of L-methionine)

L-Homoserine (2 mol) was suspended in 900 ml of acetic anhydride andadmixed with a spatula tip full of dimethylaminopyridine (DMAP). It wasslowly heated to 60° C. After approximately 1 hour, the temperaturerapidly increased to 100° C. Subsequently the reaction mixture wasstirred at 80° C. for 90 minutes and concentrated to dryness undervacuum. The resultant yellow oil was taken up in isopropanol (600 ml)and allowed to stand overnight at 0° C. The resultant crystals werefiltered off, washed with cold isopropanol and dried under vacuum. Theyield was 60% N-acetyl-2-amino-4-butyrolactone isolated, the purity 99%(according to HPLC).

Subsequently the N-acetyl-2-aminobutyrolactone (1 eq) was reacted withvarious bases in MeSH to give N-acetylmethionine. A mixture ofN-acetylaminolactone, base and MeSH (14 eq) was heated in a sealedautoclave. After cooling, expansion and removal of MeSH, the remainingoil was analysed by HPLC. Further details and the yield ofN-acetyl-L-methionine achieved are listed in the table below:

Equivalent with Yield of Base/Case respect to Temperature Time N-acetyl-a) to e) starting material (° C.) (h) L-met (%) a) NMe₃ 14 140 2.5 24.5%b) NEt₃ 14 140 7 19% c) TMG* 1 70 2.5 30.8% d) TMG* 10 70 2.5 57.8% e)TBD** 1 70 2.5 88.0% *Tetramethylguanidine,**1,5,7-Triazabicyclo[4.4.0]dec-5-ene

1. A method for producing L-methionine, D-methionine or a mixture of L—and D-methionine starting from homoserine, comprising convertingL-homoserine, D-homoserine or mixtures of L- and D-homoserine of theformula I:

to methionine by chemical transformation, without passing through any ofthe intermediates N-carbamoylhomoserine, 4—(2-bromoethyl)hydantoin and4—(2-methyl-thioethyl)hydantoin; wherein the chemical transformation ofL—and/or D-homoserine is carried out in a manner that comprises: a)using an acylating agent to produce N-acyl-L—and/or D-homoserine lactoneof the formula VIII:

 where R is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, tertbutyl, phenyl, mono-, di- or trihaloalkyl, wherehalogen=F or Cl, CF₃ or CCl₃, benzyloxycarbonyl or C₁— toC₄-alkyloxycarbonyl, b) reacting the N-acylhomoserine lactone obtainedin step a) with MeSH in the presence of a basic or acid catalyst to giveN-acylmethionine of formula VII:

c) hydrolyzing the N-acylmethionine obtained in step b) at temperaturesof >95° C. to give methionine.
 2. The method of claim 1, wherein saidmethod is used to produce L-methionine from L-homoserine.
 3. The methodof claim 1, wherein said method is used to produce D-methionine fromD-homoserine.
 4. The method of claim 1, wherein R is hydrogen.
 5. Themethod of claim 1, wherein R is methyl, ethyl or n-propyl.
 6. The methodof claim 1, wherein, in step a), said acylating agent is of the generalformula R—CO—X¹, where X¹ can be R¹COO, OR² (R² ⁼methyl or ethyl), Cl,Br, and R and R¹ can be identical or different and are selected fromhydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, phenyl, mono-, di- or trihaloalkyl, where halogen=F or Cl,CF₃ or CCl₃, benzyloxycarbonyl, or C₁- to C₄- alkyloxycarbonyl,preferably tert-butyloxycarbonyl, or methyloxycarbonyl.
 7. The method ofclaim 6, wherein R and R¹ are hydrogen.
 8. The method of claim 6,wherein R and R¹ are selected from the group consisting of methyl,ethyl, n-propyl.
 9. The method of claim 6, wherein X¹ is R¹COO.
 10. Themethod of claim 6, wherein X¹ is OR².
 11. The method of claim 1,wherein, the reaction in step b) is carried out in the presence of abasic catalyst selected from the group consisting of: NaOH; KOH;pyridine; trimethylamine; triethylamine; or an acetate, carbonate orhydrogencarbonate of an alkali metal or alkaline earth metal; tertiaryamines having a maximum of 36 carbon atoms and 1 to 4 nitrogen atoms,tetra(C₁—C₄-alkyl)guanidine, bicyclic amines, preferably DBU(1,8-diazobicyclo[5.4.0]undec-7-ene) and TBD(1,5,7-triazabicyclo[4.4.0]dec-5-ene), and pyridine.
 12. The method ofclaim 1, wherein, the reaction in step b) is carried out in the presenceof a strongly alkaline ion-exchange resin.
 13. The method of claim 1,wherein, the reaction in step b) is carried out in the presence of aBrönstedt acid selected from the group consisting of: HCl, HBr, HI,H₂SO₄, alkali metal HSO₄, H₃PO₄, alkali metal H₂PO₄, where alkali metalis lithium, sodium, potassium, rubidium or cesium, polyphosphoric acid,C₁—C₁₂-alkylsulphonic acid, C₆—C₁₀-arylsulphonic acid,trifluoromethanesulphonic acid, trifluoroacetic acid, or a copolymer oftetrafluoroethylene and perfluoro-3,6-dioxo-4-methyl-7-octenesulphonicacid (Nafion).
 14. The method of claim 1, wherein, the reaction in stepb) is carried out in the presence of a Lewis acid selected from thegroup consisting of: AlCl₃, ZnCl₂, BF₃·OEt₂, SnCl₂, and FeCl₃.
 15. Themethod of claim 1, wherein the reaction in step b) is carried out in thepresence of a strongly acidic ion-exchange resin.
 16. The method ofclaim 1, wherein, the reaction in step b) is carried out in the presenceof a heterogeneous acid catalyst selected from the group consisting of:(WO₃- and Cs₂O)-containing aluminium oxide, zeolite andmontmorrillonite.
 17. The method of claim 1, wherein the reaction instep b) is carried out in solution and/or in suspension in an organicsolvent.
 18. The method claim 1, wherein said the reaction in step b) iscarried out in a solution and/or suspension in the presence of waterand/or an organic solvent selected from the group consisting of: C₃ toC₆ ketones; straight-chain or branched C₁ to C₄ alcohols; C₄ to C₁₀carboxylic esters; C₃ to C₆ carboxamides; C₆ to C₁₀ aromatics; and C₃ toC₇ cyclic carbonates.
 19. The method of claim 1, wherein said methodutilizes only homoserine having an L configuration and produced byfermenting bacteria of the genus Corynebacterium or Escherichia.
 20. Themethod of claim 1, wherein said method utilizes only homoserine having aD configuration and produced by fermenting bacteria of the genusCorynebacterium or Escherichia.